JPS6047272B2 - 1-Nitrophenyl-4-oleamido-pyrazolo[3,4-d]pyrimidine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new substance, 1-nitrophenyl-4-oleamidopyrazo[3,4-d]pyrimidine, which has excellent suppressive action.

As is well known, cancer treatments include surgery to remove cancer cells and surrounding tissue, radiotherapy to destroy cancer cells with radiation, and chemotherapy. Various anticancer drugs have been developed.

In particular, many pyrimidine derivatives and purine derivatives that antagonize pyrimidine metabolism and purine metabolism involved in nucleic acid synthesis have been developed as substances with suppressive effects, and some of these compounds are effective in inhibiting the proliferation of cancer cells. Although many of the conventional anticancer drugs have serious side effects, the mainstay of cancer treatment is surgery and radiation therapy, and chemotherapy drugs are used in combination with these as an auxiliary measure. The current situation is that However, even if cancer cells are surgically removed, there is still a possibility that they will metastasize throughout the body, and if they have metastasized throughout the body, it is difficult to treat them with just local excision, and therefore anticancer drugs may not be effective. Chemotherapy, which treats cancer by acting on cancer cells to inhibit their proliferation, is expected to become the mainstream of cancer treatment, and there is a demand for the development of substances with excellent suppression effects for use in this treatment.

In view of the above circumstances, the present inventors have developed pyrazolo [3, 4-d]
As a result of various studies on pyrimidine compounds, we found that 1-nitrophenyl-5-amino-4-cyanopyrazole obtained by reacting nitrophenylhydrazine and ethoxy J methylenemalononitrile was reacted with formamide to produce 1-nitrophenyl-4-amino- Pyrazolo [3,4-
d] When pyrimidine is obtained and reacted with various acid chlorides, 1-nitrophenyl-4-aminopyrazolo[
3,4-d] New derivatives of pyrimidine were synthesized using nitrophenylhydrazine in which the nitro group is in the meta or para position and oleoyl chloride as the acid chloride. We have discovered that 1-nitrophenyl-4-oleamide pyrazolo[3,4-d]pyrimidine has a specifically excellent anticancer effect and has low toxicity, leading to the present invention. .

That is, the present invention provides a novel substance, 1-nitrophenyl-4-oleamidopyrazolo[3,4-d]pyrimidine, which has excellent anticancer effects and is useful as an anticancer agent. The present invention will be explained in detail below.

The 1-nitrophenyl-4-oleamidopyrazolo[3,4-d]pyrimidine according to the present invention is represented by the following chemical structural formula (1).

(In the formula, the nitro group is at the meta or rose position.

) This compound is a colorless needle-like crystal, and its melting point is P-
The temperature for the nitrophenyl derivative is 105-106 and the temperature for the nitrophenyl derivative is 94-95°C.

Incidentally, FIG. 1 and FIG. 2 show the infrared absorption spectrum and nuclear magnetic resonance spectrum of l-p-nitrophenyl-4-oleamidopyrazolo[3,4-,d]pyrimidine, respectively. Among the compounds represented by the above formula (1), p
- The nitrophenyl derivative has p as shown in formula (a).
-Nitrophenylhydrazine and ethoxymethylenemalononitrile are reacted in an ethanol solvent to synthesize 1-p-nitrophenyl-5-amino-4-cyanopyrazole (chemical structural formula (2)), and formamide is reacted with this. 1-P-nitrophenyl-4-aminopyrazolo[3,4-d]pyrimidine (chemical structural formula (3)) was synthesized using Ru.

Furthermore, the m-nitrophenyl derivative is synthesized in the same manner as in formula (a) using m-nitrophenylhydrazine instead of p-nitrophenylhydrazine. (However, R
indicates ゝd−(″゛.

) Therefore, the compound represented by the formula (1) has an excellent cancer cell proliferation inhibiting effect. Among these compounds, for example, p-nitrophenyl derivatives have an LD5O value of 10
00m9/Kg mouse (oral administration) or more, its toxicity is quite low, and the compound is stable.
This compound can be formulated by conventional means, and as mentioned above, tumor can be effectively inhibited by administration of this compound, and it has an excellent anticancer effect, so it is useful as an anticancer agent. A production example of this compound (1) will be shown below, taking 1-P-nitrophenyl-4-oleamidopyrazolo[3,41d]pyrimidine as an example.

[Manufacturing example]

3.06 da of p-nitrophenylhydrazine was dissolved in 10 ml of ethanol and kept at 40°C.

A solution obtained by dissolving 2.44 y of ethoxymethylenemalononitrile in 3 ml of ethanol was gradually added to this with stirring, and the mixture was reacted at 60 to 70°C for 2 hours. The reaction solution was then cooled on ice, and the precipitated crystals were collected and recrystallized from ethanol to give 3.85 g of 1-P-nitrophenyl-5-amino-4-cyanopyrazole (yield: 80.1%).
I got it. The properties of this compound were as follows. Appearance: Colorless needle crystals Melting point: 217-218°C Next, 7.0y of formamide was added to 2.30f of 1-P-nitrophenyl-5-amino-4-cyanopyrazole, and after refluxing with stirring, 15ml of water was added. In addition, the precipitated crystals were collected, washed with methanol, and then recrystallized from pyridine to obtain 1-P-nitrophenyl-4-aminopyrazolo[3,4-d]pyrimidine 3.80V (yield 88.8%).
) was obtained.

The properties of this compound were as follows. Appearance: Yellow powder Melting point: 306-30TC Next, 0.5y of 1-p-nitrophenyl-4-aminopyrazolo[3,4-d]pyrimidine was added to 40m of pyridine.
1 was heated and dissolved, and 1.0 g of oleoyl chloride was gradually added thereto with stirring, followed by refluxing for 1.5 hours.

Next, pyridine was distilled off, methanol was added, and the precipitated crystals were removed. I took it. After drying, it was dissolved in 20 ml of benzene, adsorbed on 10 ml of silica gel (SlO2.NH2O), and expanded with benzene. The benzene eluate was then taken and recrystallized from benzene and methanol to give 1-p-
Nitrophenyl-4-oleamide pyrazolo [3,4
-d]pyrimidine 0.81y (yield 79.4%). The properties of this compound were as follows. Also, the first
The figure shows the infrared absorption spectrum of this compound, and Figure 2 shows the nuclear magnetic resonance spectrum. Appearance: Colorless acicular crystals Melting point: 105-106°C Elemental analysis (%): C29H4O
N6O3 (molecular weight 520.68) then 1-p
-Nitrophenyl-4-oleamide pyrazolo [3,
4-d] The anticancer effect and acute toxicity of pyrimidine will be explained with reference to the following experimental examples.

[Experimental Example 1] As shown in the following formula (b), 1-nitrophenylhydrazine and ethoxymethylenemalononitrile were synthesized from nitrophenylhydrazine and ethoxymethylenemalononitrile, and 1-nitrophenyl-5-amino-4-cyanopyrazole was synthesized in the same manner as in the above production example. 1-nitrophenyl-84-aminopyrazolo[3,
4-d]pyrimidine was synthesized and further reacted with acid chloride to synthesize various 1-nitrophenyl-4-aminopyrazolo[3,4-d]pyrimidine derivatives shown in Table 1.

On the other hand, Ehrlichi tumor cells (3X103) were subcutaneously inoculated into 25y mice (DdY), and 5 mice were
Each group was divided into a control group and a test group.

Claims (1)

[Claims] 1. 1-Nitrophenyl-4-oleoamide-virazolo [which is represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (in the formula, -NO_2 is located at either the para or meta position) 3,4-d]pyrimidine.